The current epidemic of obesity and associated health problems is presenting significant public health challenges. The identification of new therapeutic strategies for regulating energy intake, absorption, and storage is therefore an important goal. The complex community of microorganisms residing within the digestive tract (microbiota) has recently been identified as an important environmental factor that regulates host nutrient metabolism and energy storage. The presence of the gut microbiota leads to a significant increase in body fat, caused in part by microbial suppression of intestinal epithelial expression of Fasting-induced adipose factor (Fiaf/Angptl4; a circulating inhibitor of lipoprotein lipase). The microbial signals and host transcriptional regulatory mechanisms that control Fiaf expression in the intestine remain completely unknown. The long-term goal of my research program is to understand the molecular mechanisms underlying host-microbial interactions in the digestive tract. We have established a gnotobiotic zebrafish model and used it to reveal evolutionarily-conserved roles for the zebrafish microbiota on host nutrient metabolism, including intestinal epithelial suppression of the zebrafish Fiaf ortholog. The optical transparency of the developing zebrafish, as well as the amenability of the zebrafish to genetic screens, provide new opportunities for investigating the roles of the microbiota in host biology. The overall objective of this application is to exploit the advantages of the zebrafish model to identify bacterial and host factors that regulate Fiaf expression. The proposed research will address the central hypothesis that intestinal bacteria signal through host transcriptional regulatory mechanisms to suppress Fiaf and thereby alter host energy balance. The rationale underlying the proposed research is that the identification of bacterial and host mechanisms that control Fiaf synthesis will provide new targets for the manipulation of host energy storage. In Specific Aim 1, we will use a bacterial genetic approach to identify bacterial genes required for suppression of Fiaf. In Specific Aim 2, we will use zebrafish transgenesis and genetic tests to identify host transcriptional regulatory mechanisms that control Fiaf expression in the intestine. The results of this research are expected to contribute a new understanding of the bacterial genes and host transcriptional regulatory mechanisms that regulate intestinal expression of Fiaf. This contribution is significant because it is expected to vertically advance the field of host-microbial mutualism in the intestine, and lead to the development of new therapeutic strategies for regulating energy storage in humans. PUBLIC HEALTH RELEVANCE: Fat storage is influenced by the complex community of microorganisms residing in the intestine. The goal of the proposed research is to understand how intestinal microorganisms signal to their host to regulate fat storage. This new knowledge could lead to novel therapeutic approaches for prevention and treatment of obesity and related diseases.